No significant differences between the groupsOnly true subjective variable is the signs of intracranial hypertension, which is recorded as the impression as the interpreting physician
Nccu journal club 2.5.13
NCCU Journal Club JOSHUA KORNBLUTH, MD F E B 5 TH, 2 0 1 3
Objective: to review a recent randomized trial of intracranial pressure monitoring in sTBI To encourage thought and discussion of our own practices To consider future directions Nothing for me to disclose
Study Overview Does intracranial pressure monitoring improve outcomes in severe TBI? What is the current standard of care in America? Why does this question matter? Multicenter, 324 adult pts, severe TBI, randomized to two separate protocols Looked at in-hospital events, survival time and 3- and 6- month outcomes
Study Overview Can we conduct this type of study in America? Highly unlikely, so lets take advantage of alternative standards of care to investigate. Study Design Multicenter, parallel-group trial Random assignment to ICP-monitoring group vs imaging- clinical examination group Study started in Bolivian hospitals, and additional hospitals were added later to increase enrollment
Study Design – Inclusion Criteria Traumatic brain injury GCS < 8 on admission or within first 48 hours after injury (Motor score ≤ 5 if intubated) Admission to study hospital within 24 hours of injury No foreign object in the brain parenchyma. Age > 12 Randomized: within 24 hours of injury [for patients with GCS < 8 on admission] or within 24 hours of deterioration [patients deteriorating to GCS < 8 within 48 hours of injury Randomization stratified according to site, injury severity score, and age
Study Design – Exclusion Criteria GCS of 3 with bilateral fixed and dilated pupils No consent Pregnant Prisoner No beds available in ICU No ICP monitor available Non-survivable injury Other (e.g., Pre-injury life expectancy under 1 year) Pre-existing neurological disability that would confound outcome
Study Design - protocol Place patient on mechanical ventilation (VM) Place continuous SaPO2 and EtCO2 monitors Insert indwelling urinary catheter to monitor urine output Insert arterial catheter for arterial mean pressure monitoring Insert central venous catheter for infusion of solutions and central venous pressure monitoring. Monitor neurological clinical status each hour Pupils GCS Brain CT To evaluate evolution 48 hours after the admission CT To evaluate evolution 5-7 days after the admission CT p.r.n.
Study Design – Standards of Critical Care Clearly delineate standard basic Critical Care• Head positioning 30º• Head and neck in neutral position and aligned• Avoid hyperthermia (Defined as central temperature > 38 º C) • Non-drug measures (cooling) • Dipirona (Metamizole sodium)• Early enteral nutritional support • Before 48 hours • 25 Kcal/kg weight• Pharmacologic prophylactic of post traumatic seizures (Phenytoin (IV or PO)) • Load and maintenance dose as is being giving in each hospital• Gastric bleeding prophylaxis • Ranitidine or Omeprazol• Avoid decubitus lesions• Deep venous thrombosis prophylaxis• Frequent tracheal suctioning with sterile technique to prevent pulmonary infections
Study Design – ICP group Had parenchymal monitor ASAP (i.e. after randomization and resolution of coagulopathy if present) Position was not specified Treat if ICP≥20mmHg x 5min If CSF drainage indicated, EVD placed CPP goal 50-70mmHg
Study Design – Treatments (ICP Group) Treatments based on a “Therapeutic Intensity Level” If signs of intracranial HTN, clinical or imaging 1 – hyperosmolar therapy (mannitol) 5% NaCl only if hypotenisve, hypovolemic, hyponatremic 2 – optional mild hyperventilation (pCO2 30-35mmHg) 3 – Ventricular drainage if possible*
Study Design – Definitions (ICP Group) Intracranial Pressure Definitions: Treatable intracranial hypertension: ICP > 20 mmHg for > 5 minutes Treatment failure: ICP not reduced to ≤ 20 mmHg within 20 minutes after a treatment intervention is initiated, and Persistent elevation in ICP > 20 mmHg requires increase in therapeutic intensity level
Study Design – “Neuroworsening” Neuroworsening = Inc’d TIL 1. Decrease in the motor GCS > 2 2. New loss of pupil reactivity 3. Interval development of pupil asymmetry of > 2mm 4. New focal motor deficit 5. Herniation syndrome Give mannitol 0.25-1mg/kg to sOSM<320 Hyperventilate to pCO2 25-30 If no response thiopental x 3d Craniectomy for space-occupying lesions
Study Design – Imaging only Group After optimized sedation and analgesia, hyperventilation and hyperosmotic therapy should be started simultaneously if there is evidence of edema on CT, as indicated as following: 1. Compressed peri-mesencephalic cisterns 2. Midline shift 3. Cortical sulcal compression / effacement Otherwise, same metrics and goals of ICP monitored group Corticosteriods prohibited AED’s for prophylaxis >28d
Study Design - Outcomes Primary outcome – 21-point composite of survival, duration and level of impaired consciousness, 3- month GOSe and GOAT, 6-month GOSe and neuropsych testing Secondary Outcomes – ICU LOS, number of days that patients received at least 1 brain-specific treatment, days of MV, treatment with high-dose barbiturates, decompressive crani
Results MVA’s accounted for most injuries (51% of randomized pts) 45% of pts were brought in by ambulance Remainder were transferred from other facilities Did not publish pre-hospital demographics or interventions as these we not uniformly recorded
Results - Demographics 24% of randomized patients had clinical decline to GCS within eligibility criteria 49% of patients had localizing signs on clinical exam 33% of participants required surgical treatment of mass lesions On initial CT, 85% had cisternal compression and 36% had >5mm midline shift
HR for death at 6mos =1.10,slightly in favor of ICP group
Results – Subgroup Analysis Hospital LOS was slightly shorter in the ICE group (iqr 12 for ICP, 9 for ICE) No significant differences in MV days, of non-neurologic complications Except ICP-monitored pts had a higher incidence of decubitus ulcers (12%vs 5%, P=0.03) Median time of ICP monitoring was 3.6d Incidence of Neuroworsening after randomization was 25% in the entire study, and was similar in both groups Median interval for brain-specific treatments was longer in ICE group Use of barbiturates was significantly higher in the ICP group (24% vs 13%) HTS and HV were used more in the ICE group (72% vs 58%, 73% vs 60%)
Results Almost every variable, including LOS, mortality, anf functional outcomes favored ICP monitoring with a HR>1. The study was powered to detect statistical significance of HR>1.5 Subgroup analysis of HR accounting for Marshall CT Classification
Results Summary Composite endpoints between the two groups were similar (P=0.49) ICP group = 56 ICE group = 53 Mortality at 6 months (P=0.06) ICP group=39% ICE group=41% ICE group had more days of brain specific treatments (hyperosmolar therapy, HV)
Discussion So what did the trial show? Clinicians act on ICP, without clinical correlate as evidenced by the increased use of barbiturates Clinicians also act on clinical findings without quantitative evidence of intracranial hypertension as evidenced by more brain-specific treatments overall in the ICE group. Is this because increased ICP could herald clinical changes and early interventions abort herniation events? Also, radiographic signs may not translate to the parenchymal monitor.
Discussion - Skepticism South America – differences in pre-hospital, and post- hospital care Less might survive to hospital or to hospital transfer Rehabilitation standards are different and may not translate to the same cognitive recovery 35%death in all groups after 14d Adjusted estimates of sTBI mortality in the US varies from 41%-25% (J Neurotrauma. 2012 Jan 1;29(1):47-52., J Neurotrauma. 2012 Jan 1;29(1):47-52.) The “Thereapeutic Intensity Level” is a good overall metric but others such as %responders to ICP-lowering therapy has proven predictive and should have been incorporated (J Neurosurg. 2011 May;114(5):1471-8)
Discussion - Skepticism Technology – parenchymal monitors as standard Triggers for treatment? – ICP>20 x 5 min vs radiographic signs with or without clinical correlates ICP group – ICP triggers ICP is too simplistic a reflection of intracranial pathophysiology. No account for CPP Clinical signs don’t always reflect global pressures and vice versa No discussion of inclusion/exclusion of polytrauma and surgical interventions
Discussion - Skepticism Variability in treatments (i.e. more mannitol and HV in the ICE group) may be because the ICE group had scheduled scans and interventions and the ICP group had more event-related treatment triggers Conversely, that may explain why the ICP group had more barbiturates and HTS
Discussion - benefits Very rigorous treatment algorithm for management of elevated ICP (either qualitative or quantitative) Homogenous population across countries Both groups had intracranial HTN treated… that isn’t in question In truth, this study did not test ICP monitoring, only a very specific treatment algorithm to an ICP threshold compared with clinical exam In the end, the neurologic exam might STILL be the best tool in our disposal.
Further Discussion This was probably the only way that this type of trial could be done Authors were careful not to compare South American patients to our own, only report their findings The goal of therapies was to lower the average ICP within the head – this doesn’t accurately reflect mechanical compression and injury to diepnephalic which may portend a worse prognosis. The clinical signs of elevated ICP (pupil dilations, posturing, coma) are directly related to these areas.
Further Discussion How would you alter the study? Could multimodal monitoring be the next step? Are composite endpoints more useful that single variable? i.e. mortality? Return to work? Is a 6-month outcome long enough? Don’t forget that even the most rigorous study cannot account for all possible variables and that this data might not apply to every patient.